Cisatracurium besylate has the chemical name (1R,1′R,2R,2′R)-2,2′-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-isoquinolinium dibenzenesulfonate and is represented by the structural formula (I) below:

Cisatracurium besylate is the dibenzenesulfonate salt of 1R-cis,1′R-cis isomer of atracurium. The atracurium compound has four chiral centers resulting in 16 possible isomers. Due to the symmetry of the molecule, the number of isomers is reduced to 10. The possible isomers of atracurium are detailed by J. B. Stenlake et al. in “Biodegradable neuromuscular blocking agents”, Eur. J. Med. Chem.—Chem. Ther., vol. 19, issue 5, pp. 441-450 (1984).
Cisatracurium besylate is a nondepolarizing neuromuscular blocking agent indicated for inpatients and outpatients as an adjunct to general anesthesia, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation in the Intensive Care Unit (ICU). Cisatracurium besylate possesses an activity that is superior to atracurium besylate, with significantly less side effects.
Cisatracurium besylate is marketed in the United States and Europe by Glaxo and Abbott Laboratories under the trade name Nimbex®. Nimbex® is a sterile, non-pyrogenic aqueous solution that is adjusted to pH 3.25 to 3.65 with benzenesulfonic acid. The drug is provided in 2.5 ml, 5 ml and 10 ml ampules having a strength of 2 mg/ml cisatracurium besylate. In addition, a 30 ml vial containing 5 mg/ml cisatracurium besylate is also available.
Cisatracurium besylate slowly loses potency with time at a rate of approximately 5% per year under refrigeration (5° C.). Nimbex should be refrigerated at 2° to 8° C. (36° to 46° F.) in the carton to preserve potency. The rate of loss in potency increases to approximately 5% per month at 25° C. (77° F.).
Atracurium besylate, otherwise known as 2,2′-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-isoquinolinium dibenzenesulfonate, was first disclosed in U.S. Pat. No. 4,179,507 (hereinafter U.S. '507). U.S. '507 describes a series of bis veratryl isoquinolinium quaternary ammonium salts, preferably among them is atracurium besylate. The synthesis of atracurium besylate, as taught in U.S. '507, involves the coupling of (±)-tetrahydropapaverine base (compound II), with 1,5-pentamethylene diacrylate (compound III). Treatment of the resulting tertiary amine base with oxalic acid results in the isolation of N,N′-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropapaverine dioxalate (compound IV). The dioxalate salt (compound IV) is converted to the free base (compound V), which is treated with methyl benzenesulfonate. The resulting product, atracurium besylate (compound VI), is precipitated and isolated. Scheme 1 below illustrates the chemical pathway described above.

U.S. '507 discloses that the stereoisomerism of atracurium besylate (VI) may be partly controlled by controlling stereochemical configuration of compound (II) to provide the tertiary amine base (V) of a RR—, SS—, or RS— (meso) configuration. The quaternization process introduces 2 additional centers of asymmetry resulting in the formation of a mixture of stereoisomers. U.S. '507 does not describe separating stereoisomers from the mixture.
Cisatracurium besylate is disclosed in U.S. Pat. No. 5,453,510 (hereinafter U.S. '510). U.S. '510 describes the formation of (R)-tetrahydropapaverine (compound IIA) from compound (II) which is converted into a mixture of R and S diastereoisomer salts with the chiral amino acid, N-acetyl-L-leucine, resulting in the formation of a mixture of 83% of the R and 17% of the S diastereoisomer. Crystallization of the mixture from acetone affords 97% (R)-tetrahydropapaverine-N-acetyl-L-leucinate and 3% (S)-tetrahydropapaverine-N-acetyl-L-leucinate which is converted into (R)-tetrahydropapaverine base. The (R)-tetrahydro-papaverine is subsequently reacted with 1,5-pentamethylene diacrylate followed by oxalic acid to afford the dioxalate salt of (1R,1′R)-2,2′-(3,11-dioxo-4,10-dioxatridecamethylene)-bis-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-veratrylisoquinoline) (i.e., an isomer of compound IV). Conversion of the dioxalate salt into the free base, followed by treatment with methyl benzenesulfonate, affords an aqueous solution of (1R,1′R)-atracurium besylate. Lyophilization results in a pale yellow solid that includes a mixture of three isomers, namely, (1R-cis,1′R-cis); (1R-cis,1′R-trans); (1R-trans,1′R-trans), (hereinafter referred to as the “atracurium besylate mixture”), in a ratio of about 58:34:6 respectively. The atracurium besylate mixture is subjected to preparative HPLC column chromatography on silica using a mixture of dichloromethane, methanol and benzenesulfonic acid in the ratio of 4000:500:0.25 as the eluent. The fractions containing the required isomer are collected and washed with water. The dichloromethane solution is evaporated to dryness, the residue dissolved in water and the pH of the solution adjusted to 3.5-4.0 with an aqueous solution of benzenesulfonic acid. The aqueous solution is lyophilized to afford cisatracurium besylate possessing an isomeric purity of about 99%.
U.S. Pat. No. 5,556,978 (hereinafter U.S. '978) recites a process for the preparation of cisatracurium compounds, including cisatracurium besylate, using high performance liquid chromatography with a silica stationary phase and a non aqueous mobile phase in the presence of a strong acid. The resulting product may contain less than 2% w/w of other geometrical and optical isomers based on the total weight of the relevant mixture.
The above procedures suffer from several disadvantages. A major problem in the procedures is attributable to the HPLC purification step. The need for HPLC purification is undesirable in a large-scale operation because only relatively small amounts of product can be purified at a time; it is expensive, time-consuming and generates large quantities of waste, e.g., waste solvents. This means that considerations with regards to safely disposing of the accumulated wastes are necessary. A further disadvantage with the above procedures is that cisatracurium besylate may be unstable in the eluent mixture used in the HPLC separation and, thus, can lead to the formation of decomposition products.
There is, therefore, a need for an improved process for the production of cisatracurium, e.g., cisatracurium besylate, and intermediates therefor. It is desirable that the procedure avoids, where possible, the need for purifying the intermediates as well as the cisatracurium product by column chromatography. It is also desirable that the process can be scaled up to enable the large scale production of cisatracurium.